Project Summary/Abstract Obesity is well-recognized to be a strong risk factor for cancer development and progression, likely acting through various growth-enhancing hormones and inflammation. Although weight management of obesity is generally encouraged by clinical guidelines, weight control can be particularly frustrating in general, and even for highly motivated cancer patients. Further, unintentional weight loss, which is associated with poor survival, could be problematic in cancer patients (`obesity paradox'). Therefore, focusing on dietary pattern and physical activity instead of weight loss may be a more feasible approach to prevent or minimize the obesity-associated mediators of carcinogenesis for cancer patients. However, the current understanding on the role of diet and physical activity in cancer survival is insufficient to provide evidence-based recommendations for cancer patients. Based on our new integrative framework, we hypothesize that low pro-inflammatory/hyperinsulinemic diets and high physical activity after cancer diagnosis may reduce all-cause and cancer-specific mortality in patients with major obesity-related cancers, including colorectal, endometrial and prostate cancer. Aim 1 will examine the association of postdiagnosis pro-inflammatory/hyperinsulinemic diets with cancer survival, independent of adiposity and weight change. We will use empirically defined two dietary patterns that we recently developed and validated based on their prediction of inflammatory and insulin markers in 3 large cohorts. Aim 2 will further build on emerging evidence on the potential beneficial effect of postdiagnosis physical activity on cancer survival by examining the important aspects of physical activity (volume, type and intensity) in relation to cancer survival, independent of adiposity and weight change. Aim 3 will examine the combined association of pro-inflammatory/hyperinsulinemic diets and physical activity on cancer survival, both independently and stratified by adiposity and weight change, to better understand the potential interaction between diet and physical activity and the role of adiposity in the association. To complete these aims, we will utilize the considerable resources from two large US prospective cohort studies (Nurses' Health Study and Health Professionals Follow-up Study), which are among the few cohorts worldwide that have collected both pre-and post-diagnosis data. In summary, the proposed study has great potential to provide unique insights into the integrative role of pro-inflammatory/hyperinsulinemic diets, physical activity and adiposity in survival among patients with major obesity-related cancers. This study will serve as a promising step towards development of clinically feasible strategies to improve future cancer survival, facilitate research directed to assessing the effect of pro-inflammatory/hyperinsulinemic diets and physical activity, and generate new evidence to inform weight and lifestyle guidelines for cancer survival.